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Anorexia Nervosa from Single SNP Studies, Through Biomarkers, to Genome-Wide Association

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Anorexia Nervosa from Single SNP Studies, Through Biomarkers, to Genome-Wide Association Anorexia nervosa From single SNP studies, through biomarkers, to genome-wide association Marek K. Brandys ISBN: 978-94-6182-640-4 Printed by: Offpage, Amsterdam Layout: Marek K. Brandys Cover design: Marek K. Brandys, based on Effect of Butterfly by Anastasiya Markovich (Picture Labberté K.J.) via Wikimedia Commons © Marek K. Brandys Anorexia nervosa From single SNP studies, through biomarkers, to genome-wide association Anorexia nervosa Van SNP studies via biomarkers naar genoomwijde associatie (met een samenvatting in het Nederlands) Anorexia nervosa Od badań polimorfizmów pojednynczego nukleotydu, przez biomarkery, po badania asocjacyjne całego genomu (ze streszczeniem w języku polskim) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op dinsdag 19 januari 2016 des ochtends te 10.30 uur door Marek Kajetan Brandys geboren op 27 november 1983 te Kraków, Polska (Polen) Promotoren: Prof. dr. R.A.H. Adan Prof. dr. A. van Elburg Copromotoren: Dr. M.J.H. Kas Dr. C. de Kovel This thesis was partly accomplished with financial support from the Marie Curie Research Training Network INTACT (Individually tailored stepped care for women with eating disorders; reference number: MRTN-CT-2006- 035988) Table of contents CHAPTER 1 ................................................................................................................................... 6 Introduction Scope and outline of the thesis CHAPTER 2 ................................................................................................................................. 35 Are recently identified genetic variants regulating BMI in the general population associated with anorexia nervosa? CHAPTER 3 ................................................................................................................................. 46 Association study of POMC variants with body composition measures and nutrient choice CHAPTER 4 ................................................................................................................................. 69 Anorexia nervosa and the Val158Met polymorphism of the COMT gene: meta-analysis and new data CHAPTER 5 ................................................................................................................................. 90 A meta-analysis of circulating BDNF concentrations in anorexia nervosa CHAPTER 6 ............................................................................................................................... 129 The Val66Met polymorphism of the BDNF gene in anorexia nervosa: new data and a meta- analysis CHAPTER 7 ............................................................................................................................... 164 No evidence for involvement of CNVs associated with neurodevelopmental disorders in anorexia nervosa APPENDIX ................................................................................................................................ 193 A genome-wide association study of anorexia nervosa CHAPTER 8 Discussion and conclusions................................................................................... 226 Overview of genetic research in anorexia nervosa: the past, the present and the future Concluding remarks ADDENDUM ............................................................................................................................ 264 English summary Nederlandse samenvatting Streszczenie w języku polskim Curriculum Vitae List of publications Acknowledgements Chapter 1 Chapter 1 Introduction The main focus of the present thesis is to describe the scientific undertaking of exploring the genetic underpinnings and biomarkers of anorexia nervosa (AN). We begin by introducing the history, intricate phenotypic manifestations, as well as the clinical and epidemiological characteristics of this intriguing disease. According to DSM-5 AN belongs to the category of feeding and eating disorders (ED), under the code 307.1 (F50.01) for AN restricting type and (F50.02) for the binge-eating/purging type. Other classes in this category include bulimia nervosa (BN; 307.51 (F50.2)), binge eating disorder (BED; 307.51 (F50.8)), other specified feeding or eating disorder (OSFED; 307.59 (F50.8)) and unspecified feeding or eating disorder (307.50 (F50.9)). Diagnostic criteria of AN, according to DSM-5, are listed in a later section. History It was a British royal physician, Sir William Gull, who in 1873 established the term ‘anorexia’ (derived from Greek ‘an-’, meaning negation, and ‘orexis’, signifying appetite) 1. The first medical descriptions of cases with AN are dated earlier than that, and ascribed to Richard Morton, also a British physician. Looking even further back, there exist historical accounts of people who appear to have suffered from this disorder. In the ancient Hellenistic culture fasting and self-starvation were seen as expressions of religious zealousness. While only a few reports are available from the medieval ages, a larger number of descriptions of the possible cases of AN comes from the times of the Renaissance. Religious ascetics would forge their way to sanity via starvation, self-mutilation and social isolation 2. A 6 Chapter 1 number of historical figures are suspected to have suffered from AN, such as Saint Catherine of Siena, Mary, Queen of Scotts or Elisabeth, Empress of Austria (source: http://divainternational.ch/spip.php?article97). In the modern times, a general interest in AN surged after the death of a famous musician, Karen Carpenter (4 February 1983). Somatic health risks The most striking feature of the patients suffering from AN is their low body- weight (85% or less than the weight expected). This symptom is accompanied by a refusal to consume sufficient amount of calories – an amount necessary to prevent further emaciation and restoration of the body weight to the normative levels. This continuous undernourishment damages body systems and, in extreme cases, leads to death. Serious medical complications associated with malnutrition in AN include: ° Reduced heart rate and low blood pressure, entailing increased risk of heart failure ° Amenorrhea in post-pubertal females (lack of menstruation) ° Osteoporosis (decreased bone density) ° Loss of muscles ° Dehydration, possibly leading to kidney failure ° Fainting, fatigue, general weakness ° Hair loss, changes of complexion, growth of lanugo – a thin hair layer covering the body Furthermore, health risks associated with the purging behaviors present in the purging subtype of AN include: ° Electrolyte imbalance (caused by dehydration, loss of potassium, chloride and sodium), possibly leading to a heart failure ° Inflammation and possible rupture of esophagus (as a result of vomiting) ° Tooth decay ° Constipation and chronic irregular bowel movements, coming from abuse of laxatives (source: 7 Chapter 1 http://www.nationaleatingdisorders.org/nedaDir/files/documents/h andouts/HlthCons.pdf) Criteria and symptoms These serious somatic complications are paralleled by the devastation which the disease incurs to the psyche. Suicide is the most frequent cause of death in EDs 3. There is a 57-fold increase in risk of death from suicide among patients with AN, compared to the age-matched cohort 4. Individuals with AN are characterized by the immense fear of weight (fat) gain and disturbed body image. The criteria for diagnosis of AN established in the 5-th edition of The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) are presented below: A. Restriction of energy intake relative to requirements leading to a significantly low body weight in the context of age, sex, developmental trajectory, and physical health. B. Intense fear of gaining weight or becoming fat, even though underweight. C. Disturbance in the way in which one's body weight or shape is experienced, undue influence of body weight or shape on self-evaluation, or denial of the seriousness of the current low body weight. Symptoms which might suggest AN (warning signs) include (after http://www.allianceforeatingdisorders.com/): • Significant weight loss • Distorted body image • Intense fear/anxiety about gaining weight • Preoccupation with weight, calories, food, etc. • Feelings of guilt after eating • Denial of low weight • High levels of anxiety and/or depression 8 Chapter 1 • Low self-esteem • Self-injury • Withdrawal from friends and activities • Excuses for not eating/denial of hunger • Food rituals • Intense, dramatic mood swings • Pale appearance/yellowish skin-tone • Thin, dull, and dry hair, skin, and nails • Cold intolerance/hypothermia • Fatigue/fainting • Abuse of laxatives, diet pills, or diuretics • Excessive and compulsive exercise Subtypes and diagnostic cross-over There are two subtypes within the category of AN: the restricting (restrictive) type (ANR) and the bingeing-purging type (ANBP). The main difference is that the individuals with the latter one experience periods of binge eating (consumption of excessive amounts of food coupled with a subjective feeling of loss of control over eating) followed by purging behaviors, which are means to compensate for the calories consumed. Purging can take forms of self- induced vomiting or/and use of laxatives, diuretics or diet pills. Patients exhibiting the restricting type do not purge, but maintain low body weight solely by reduced food intake and increased energy
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